Project Summary There is a need for new and alternative routes to generate complex structures from simple and readily available precursors under conditions that are benign and sustainable. Traditional cross coupling reactions generally have poor atom- and step-economy due to the requirement for prefunctionalized organometallic reagents, noble metal catalysts, and the separation of waste products including stoichiometric amounts of salts. The long-term goal of our research program is to replace traditional noble metal catalyzed cross-coupling reactions with first row transition metal catalysts for oxidative C-C bond forming reactions that employ readily available reagents and generate minimal byproducts. Such a goal requires the development of a broad scope of reliable C-C bond forming reactions that are benign, efficient, selective, and predictable. The objective of the work proposed here focuses on nickel-catalyzed oxidative decarboxylative cross-coupling (ODC) reactions. The development of this methodology will represent efficient routes for the late stage functionalization of arenes to generate molecules of pharmaceutical interest. To achieve this objective, we will target the following aims: The first two aims target the development of new ODC routes to two classes of molecules of pharmaceutical importance: heterobiaryls and phenanthridinones. Decarboxylative coupling strategies are often avoided due to significant limitations in scope, in particular to ortho-nitrobenzoic acids. We hypothesize that the ortho-nitro group limitation observed with previous catalyst systems originates from a challenging transmetallation step and we propose the use of nickel catalysts paired with removable directing groups to enable efficient decarboxylative coupling. The third aim is to develop a mechanistic understanding of these catalyst systems to further broaden the substrate scope to include ODC reactions of challenging benzoic acids and C-H bonds in the absence of directing groups. The development of a predictable and reliable ODC methodology is significant because it represents an efficient route to C-C bond formation using inexpensive and readily available carboxylic acid starting materials and generates minimal waste. The efficient formation of C-C bonds is a key step in the synthesis and late-stage functionalization of pharmaceutical intermediates and end targets.